The Iong-term objective of this proposal is to test a modified version of the hygiene hypothesis, in which genetic variants of TLRs in human hosts interact with different microbial colonizers to wield a positive or negative influence on the development of asthma. This hypothesis is proposed as a new and more intricate paradigm for gene by environment interactions as determinants of susceptibility to asthma and asthma-associated allergies. The following specific aims are proposed: 1) To determine the relation of TLR2 genotypes,TLR2 protein expression and S. aureus colonization pattern to risk for the development of atopic dermatitis in children; 2) To determine the variation in airway epithelial cell activation invoked by S. aureus-derived ligands and to link the variation to TLR2 genotype, expression and/or colonization pattern; 3) To establish the influence of TLR5 SNPs on TLR5 expression in innate immune cells among children with different H pylori colonization patterns; and 4) To determine the relation of patterns of S aureus and H pylori colonization to asthma development and sensitization to asthma-related aeroallergens by age 6. Data will be obtained from nasal swabs, peripheral blood cells, exhaled breath condensates, cultured airway epithelial cell lines, and primary bronchial cells. By completing these four aims, clarification will be provided as to 1) whether S aureus colonization provides an explanation for the link between atopic dermatitis and the development of asthma and is a direct causative factor in the development of asthma; 2) whether S. aureus colonization interacts with TLR2 SNP to predispose to the AD/asthma pathway; and 3) whether H pylori colonization inhibits the development of asthma by age 6 via interaction with a TLR5 stop codon SNP and/or other SNPs. If correct, the hypothesis offers an explanation for the oft-noted differences in the relation of human gene variants to asthma prevalence in different regions of the world and for the increase in asthma affecting a large portion of the world.